1. A major objective will be to determine how selenium maintains liver cytochrome P-450 and prevents the induction of heme oxygenase (HO) and increased hepatic heme catabolism in phenobarbital-treated rats. Parameters of heme metabolism will be studied in selenium-deficient (O Se) and control rats. Also selenoproteins, labeled with 75Se, will be isolated from subcellular fractions having HO activity and studied to learn whether they are involved in heme metabolism. Another objective will be to determine whether in vivo drug metabolism is affected by selenium deficiency. O Se and control rats will be given antipyrine and phenylbutazone and their T 1/2 in plasma will be determined. 2. O Se rats are more susceptible to mercury poisoning than are controls. O Se rats cannot accumulate inorganic mercury in their kidney metallothionein (MT) normally. A major objective will be to determine whether failure of the kidney mercury accumulation leads to higher levels in other tissues as an explanation for the increased toxicity. This will be carried out by measuring tissue mercury in O Se and control rats exposed to mercury. Another major objective will be to study the two forms of MT to determine why no mercury accumulation occurs. They will be purified from O Se and control rats and characterized with respect to quantity and Se and Hg content. Synthesis rates of the two forms will be studied in kidney and liver using incorporation of 35 Scystine after induction by Hg and Co. 3. We have observed a previously unrecognized GSH-Px activity in rat liver which is apparently not selenium dependent. We plan to purify and characterize this activity by conventional methods. In addition, we will determine its tissue distribution in several species. Another objective is to determine its physiological significance. Function of GSH-Px will be determined by GSSG release from perfused livers. The selenium-dependent FSH-Px will be absent from O Se livers so function of this new GSH-Px can be determined in them.